By: Farhiya Elmi

Introduction:


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Every now and then, it might be hard at times to talk about the well-known American musician Woody Guthrie, without associating him with Huntington’s disease (HD). In addition to this, a further exposure of HD in the media is the tragic case trial of Carol Carr. She was a mother from Georgia, who shot both her sons dead on the 8th of June 2002 in their nursing room, after they had reached the final progressive stage of Huntington’s disease. However all we obtain from these media coverage is that Huntington’s disease along with other complications it presents eventually leads to death; but how far do we recognize the underlying mechanisms and outcomes of this fatal disease? Originally identified as Huntington’s chorea (since patients exhibited irregular dance movements), Huntington’s disease is now understood as belonging to the neurodegenerative disorders category; revealing itself as an autosomal dominant disorder[1].Historically, this disease was not familiar to the individuals whom it had manifested in, as well as the medical consultants who were medicating these patients; they did not know what to make of it. Furthermore, they were also unaware that this illness pertained to the category of inherited neurological diseases, all originating from comparable kind of genetic alteration (poly glutamine amplification)[3]. It was only recently that it was brought to the attention of the researchers that the biological establishment of HD, in particular, the misfolding of the polypeptide, would appear as a universal theme, connecting collectively all the major neurodegenerative disorders. The neurodegenerative disorders category, in which HD is a part of, includes in addition to other diseases Parkinson’s Disease, Alzheimer’s Disease and Prions diseases [3]. With the detection of the gene in 1993, the underlying research for the mechanism of the gene responsible for HD was able to transpire [3,4]. As this disorder is progressive; gradually leading to fatality [1,18] and currently without a treatment, it is imperative for it to receive more focus. In the majority of the cases, the onset of the disease, is during adulthood(ages 21-51)[1]; by then most of the carriers are unaware they inherited the allele. As a result, they continue to live a normal life and pass the affected allele to future generations. The manifestation of the diverse abnormalities of this illness is due to the repeats of glutamine along the IT15 gene located at chromosome 4[1]. Due to the degeneration in various brain structures of these patients, they tend to lose the ability to control their bodily movements. In addition; these patients often demonstrate signs of reduced cognitive ability and behavioral changes (for example irritability and aggression).

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1.1.Genetic characteristics:
1.1.1. The role of the IT15 gene, the amplification of CAG duplication and inheritance:
University of Utah. Genetic Science Learning Center.
University of Utah. Genetic Science Learning Center.

Majority of the complications related to HD are rooted in the IT15 gene located in chromosome 4. This is the gene responsible for producing the IT15 protein (also known as Huntingtin protein)[2,5]. It is estimated to consist of around 50 amino acids [3]. The mutant form of the allele which results in the autosomal dominant disorder is said to have a glutamine repeat size which is greater than 35 located within the initial exon of the DNA (next to the N-terminal of the polypeptide) which encodes for the Huntington protein[2,11].Differentiation in the conformational variances of the protein, caused by the trinucleotide repeats, modifies the binding sites of the protein [2]. Some researchers have also used the acronym Htt exchangeably with IT15 when referring to both the gene and protein product. Namely, the mutation responsible for these various disruptions is the repetition of CAG (glutamine) along the gene[6]. The mutation in the sequence of this protein yields a polyglutamine tract which in return orchestrates and produces the toxicity of the neurons [9]. Mutation in this gene can also result in various pathogenesis and alteration to brain structures [2].Some studies have found the manifestation of this illness to be influenced by the sex of the parent who has inherited it[5].Contrary to this, additional findings suggested that among those who express the disease later in their lives (manifestations of HD initially observed at the age 50 or older) more of these patients receive the gene from the affected mother rather than the affected father [5]. Seeing as this gene has a dominant affect it tends to be present in every generation as shown in the pedigree of families who have been affected by it.
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1.1.2. Molecular and structural disturbances caused by DNA alteration in the IT15 gene:

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Beal, M.Flint and Ferrante, Robert. Neuroscience 5 , 373- 384 (May 2004)
Beal, M.Flint and Ferrante, Robert. Neuroscience 5 , 373- 384 (May 2004)

To comprehend the underlying mechanism, neurological deficits and pathologies of HD, mouse models and post-mortem brains were used by various researchers in their studies. In an experiment done by Gabriele Schilling, and her colleagues, they attempted to explain both the representation of the defected and normal Huntington protein in the brain [6]. They found with the facilitation of Western Blot that mice following 7 to 15 days after birth had the wildtype Huntington protein proliferated substantially [6]. Also mentioned in their paper during the developmental stages of the brain, the huntingtin protein is mainly localized in the neuronal perikarya[6]. By observing the brain of a 10 week- old newborn who inherited the prolonged allele of HD, they were able to notice that the mutant IT15 polypeptide appeared to be at a higher molecular mass than the normal IT15 protein [6].Based on this observation, this group of researchers was able to demonstrate that the mutant variant of huntingtin is represented in the brain prior to the completion of neuronal development [6]. The manifestation of the mutant variant or the wildtype variant appears in the brain in the early stages and during brain development [6]. Deterioration of neurons and metabolic transformations are identified to occur in the adult brain prior to the onset of the disease [6]. Having the heterozygous form of HD, both a normal and higher molecular weight of the protein is observed in the brain; this results in the increase of function due to an abnormal protein and consequently becomes the basis for the disease [6]. However what Gabriele and her group were not able to obtain from their research was when the death of the neurons took place [6]. The striatum is the area most inclined to the pathologies of HD, and in this region the mutant form of the protein is extensive with no discrepancies in expression[6].
University of Utah. Genetic Science Learning Center.
University of Utah. Genetic Science Learning Center.


The morphology of the brain as well the tissues which lie on the exterior surface of the brain are influenced by the trinucleotide duplications in the IT15 gene of HD [1],[2]. These poly glutamine (CAG) tracts in the brain, by restricting and disrupting normal brain activities can result in neurological deficits and adverse changes in the individual with HD[10]. Furthermore, the discrepancies in the expansion of the polyglutamine tracts (common to neurodegenerative diseases) can persuade regular brain organization in humans given that it contributes to differences in behavioural traits in animal models [2]. This disruption in organization of the brain is demonstrated in a study conducted by Muhlau et al. Based on their results they were able to conclude that the glutamine duplications within the IT15 gene can control normal brain organizations in humans [2]. An important trait of Huntington disease is the accumulation of the protein (HTT) which in return builds up within neurons; this characteristic of accumulation is also observed in other neurodegenerative diseases for example in Alzheimer’s disease and Parkinson's disease [17]. The aggregation of the dysfunctional IT15 protein is believed to be influenced by the span of the trinucleotide repeats, as well as the surrounding amino acids of these trinucleotiode duplications (for instance; the area rich in proline) and the form the protein takes[15] .
Elena Cattaneo, Chiara Zuccato & Marzia Tartari.Neuroscience 6, 919-930 (December 2005)
Elena Cattaneo, Chiara Zuccato & Marzia Tartari.Neuroscience 6, 919-930 (December 2005)


The wildtype HTT (also known as IT15 protein) functions to improve and regulate the vesicle transportation of BDNF (a neutrophic factor secreted in the brain) along microtubules[8]. To take part in the regulation of this transport, the huntingtin protein is connected with other proteins (HAP1 and the p150Glued; an element associated with dynactin) [8]. Hence, it was found that the distorted and aggregated form of the protein resulted in the reduction of HAP1, p150Glued,dynein IC and other proteins associated with cargo transportation [8]. In return decrease of these protein presence in the microtubules lead to decrease in intracellular transport of BDNF[8]. Here we can observe how the mutated Htt protein might operate to impair the learning process due to the loss of transport of BDNF (plays an essential part in learning by stimulating neuronal morphogenesis and differentiation).In addition to this, limitation of the BDNF transport caused by this mutation can result in lack of growth factor supply to neurons, and hence as a consequence of this is neurodegeneration takes place by the means of programmed cell death [8].
Mattson. Nature. 415, 377-379. (2002)
Mattson. Nature. 415, 377-379. (2002)
In a further study the defected IT15 protein was demonstrated to be linked with promoting the cooperation of p53 with Pin1[9]. The mutant IT15 protein activates p53 (a protein involved in tumor control, in other words it halts the cell cycle) by phosphorylation of Ser 46 (part of p53)[9]. This activity occurs downstream of the mutant IT15 protein expression [9]. Here the phosphorylation of Ser 46 causes the switch of the p53 which is normally involved in suspending the cell cycle activity, to taking part in cell death [10]. The detection of the active Ser 46 by Pin1 results in the detachment of the protein involved in cell cycle control (p53) from the apoptotic inhibitor [10]. A loss of function of Htt seen in mouse knock-out models of Htt provides evidence that the decreased presence of Htt in cells leads to programmed cell death not only in the straitum but also in the hippocampus and cortex [16].In addition to this, some researchers were able to demonstrate that the normal activity of the protein (Htt) assists in neuro-protective activities for obstacles neurons face during apoptosis [16].Also by the means of utilizing magnetic resonance imaging, various investigations in HD models have demonstrated a measurable reduction in caudate volume as time passed[6]. In other studies,the appearance of the distorted allele of HD changes the corti-costriatal glutamate discharge, by interfering in cargo transport along axons and disrupting the release and re-uptake of vesicles[14]. It has been found in these HD patients the lack of glutamate re-consumption by neurons is a result of the disturbance in function and reduction of glutamate transporter 1 expression[14].In addition to this, what is also observed in patients who express HD is the diminishing of neurons that express NMDA receptors in the striatal tissue during the initial progression of the disease [19].
In a recent study conducted by Abrez Hussain along with his colleagues, they were able to demonstrate the presence of retinal impairment in HD as the disease advanced [12]. To observe the adverse retinal alterations both in its functions and arrangements, the researchers in this study used a trans-genetic R6/1 mouse representation of HD [12]. From this mouse model, it was found that the changes in the retina were occurring simultaneously, as the other impacts of the disease progressed i.e. impairments in motor functions (hyperkinesis) [12]. The cones that are present in the retina of the R6/1 mouse were detected to be reduced in their retinal activities by the early stage of 13 weeks of age; eventually resulting in the diminishing of cone opsin and transducin[12]. Furthermore, in their study they were able to detect when the deterioration of photoreceptors occurred, the indication of relocation of rod photoreceptors terminals and modifications of rod and cone bipolar cell branches [12]. Based on their findings the researchers were able to propose that a retinal phenotype might be observed in HD; these retinal pathologies involves particular cone dysfunction, decrease in cone activity, increase retinal pressure and neuronal modifications [12].

2.1. Symptoms:

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Age of Onset, common behavioural, cognitive and physical manifestations.

Inception of HD is typically between ages 21 and 50 (most cases: 41) [5]. Those who displayed early symptoms of HD were found to have the rigid form or the Westphal variant of HD [5]. The Westphal variant is a divergent clinical category of HD. Based on the 70% of patients who possess the rigid type of HD; researchers were able to find their average onset age to be around 22.2 years of age[5]. Also seen among HD patients is the rare form that takes place in childhood [6]. For these children (accounting for 2% of the patients), the occurrence of the disease is seen between the ages 4-10 [6].Their symptoms includes; slow movements, deficit’s in their intellectual and developmental abilities, seizures and their life span is shorter that those who express the disease during their adulthood[5]. A common feature in patients who suffer from Huntington’s disease is obsessive compulsive behaviour, with an estimate account of 20% to 50% of patients[7]. However, these given rates are typically much more significant than what we see in the overall populace[7].The characteristic neuropathological modifications observed in HD are parallel to those thought to be accountable for OCD, specifically the malfunction of corticostriatal associations[7].Other mental disorder symptoms such as hallucination, suicidal thoughts, violent behavior, temper changes and melancholy may also be noticeable in HD patients[7,20].Dementia and irregular body movements (chorea) are the key symptoms that are related with HD[7].
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3.1.Prognosis:
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external image Prognosis.pngWith the repetition of 40 or more CAG repeats along the IT15 gene; virtually the full representation of the disease can be spotted at the age of 65[1,3]. There is also a correlation between age and the progression of this disease[4].In one of the research articles, researchers found age to be a confounding factor and a correlation between CAG repeats and progression of the disease with age[1].In other words, age plays an important factor along with the size of the glutamine expansion as demonstrated by the research done by Rosenblatt et.al and his colleagues to understand the rate of clinical succession of HD[1]. When controlled for the age of onset, the number of glutamine repeats might explain up to 21% of the discrepancy we see in the manifestations of disease[1]. However other studies have indicated that the span of CAG may very well not contribute to the development of the disease[4]. Due to the loss of brain structure, irregular body movements and intellectual impairment gradually worsens[5]. Longitudinal studies shows with the advancement of the disease, patients reports mentions loss in their ability to control their anger, verbal outbreaks and inability to have the flexibility in their behaviour to respond to certain stimulus[13]. Fatality usually occurs within 15-20 years of the disease onset[1] .The source for death in most of the HD patients is infection (the reason for this is still not understood); the median age of death is 54 years of age [1].

References
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2.Muhlau et al. Variationwithin the Huntington’s Disease Gene Influences Normal Brain Structure. PLoS ONE. 7(1),(2012).
3.La Spada, Albert et al.Neurobiology of Huntington’sDisease: Applications to Drug Discovery. USA; CRC PRESS (2010).
4.Ross, Christopher and Tabrizi, Sarah. Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neural.10, 83-98 (2011).
5. Rosenblatt, Adam et al . Age, CAG Repeat Length, and Clinical Progression in Huntington’sDisease. Movement Disorders.27(2), 272-276 (2012).
6. Schilling, Gabriele et al. Expression of the Huntington's disease (IT15) protein product in HD patients (Huntington 11). Human Molecular Genetics. 4(8), 1365-1371 (1995).
7. Anderson, Karen et al. Comorbidities of Obsessive and Compulsive Symptoms in Huntington's Disease. The Journal of Nerve and Mental Diseases.198 (5), 334-338 (2010).
8.Gauthier, Laurent et al. Huntingtin Controls Neurotrophic Support and Survival of Neurons by Enhancing BDNF Vesicular Transport along Microtubules. Cell. 118, 127-138 (2004).
9. Grison, Alice. Ser46 phosphorylation and prolyl-isomerase Pin1- mediated isomerization of p53 are the key events in p53 dependent apoptosis induced by mutant huntingtin. PNAS. 108(44), 17979-17984 (2011).
10.Squitieri,Ferdinandoet al.Abnormal morphology of peripheral cell tissues from patients with Huntington disease. Journalof Neural Transmisson. 117(1), 77-83 (2009).
11. Fan, Jing et al. P38 MAPK is involved in enhanced NMDA receptor-dependent excitotoxicity in YAC transgenic mouse model of Huntington’sdisease. Neurobiology of Disease.45(3), 999-1009 (2012).
12.Batcha, Abrez et al. Retinal dysfunction, photoreceptor protein dysregulation and neuronal remodelling in the R6/1 mouse model of Huntington's disease.Neurobiology of Disease.45(3), 887- 896 (2011).
13.Thompson, Jennifer et al.Longitudinal evaluations of Neuropsychiatric Symptoms in Huntington’s Disease. The Journal of Neuropsychiatry and Clinical Neuroscience. 24 (1), (2012).
14.Bezprozvanny, Ilya and Miller Benjamin. Corticostriatal circuit dysfunction in Huntington's disease: intersection of glutamate, dopamine and calcium.Future Neurobiology. 5(5), 735-756 (2010).
15. ArrasateMonstserrat and Finkbeiner Steven. Protein aggregates in Huntington’s Disease. Experimental Neurology.(2011).
16. Schulte, Joost and Littleton, J. The biological function of the Huntingtin protein and its relevance to Huntington's Diseasepathology.Current Trends in Neurology. 1(5), 65-78 (2011).
17. D, Banoet al. Neurodegenerative processes in Huntington's disease. Cell death and disease.2(11), (2011).
18. Raymond, L.A. et al. Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.Neuroscience. 15 (198), 252-273 (2011).
19. Jones, Lesley and Hughes, Alis.Pathogenic mechanisms in Huntington's disease.International Review of Neurobiology. 98, 373- 418 (2011).
20.Shang, H etal. Huntington's disease: new aspects on phenotype and genotype.Parkinsonism Related Disorders.18, S107-S109 (2012)